Cost-effectiveness analyses are integrated in evidence-based recommendations for market access and reimbursement of new products, provided by health technology assessment (HTA) bodies, in several countries. The objective was to compare economic protocols submitted for a same product to three HTA bodies, assessing if the same cost-effectiveness analysis and methodology was implemented and if the results provided consistent ICERs. We focused on the 3 following HTA bodies (Haute Autorité de Santé (HAS), National Institute for Health and care Excellence (NICE) and Canada's Drug and Health Technology Agency (CADTH)). The thirteen HAS opinions assessed from September 2021 to February 2022 were eligible for the analysis and selected if the health technology appraisal was available for the three HTA bodies. Comparison of economic protocols were performed using the published opinions for HAS, the Company evidence submission for NICE and the pharmacoeconomic reviews for CADTH. Thirteen methodological items were reviewed and compared. Among the thirteen opinions, four were available for the three HTA bodies: EVRYSDI® (spinal muscular atrophy), VENCLYXTO® (acute myeloid leukemia), KEYTRUDA® (metastatic colorectal cancer (MCC) and esophageal cancer (OC)). Eight items were common between submissions for KEYTRUDA® (MCC), seven for EVRYSDI®, two for KEYTRUDA® (OC) and one for VENCLYXTO®. Objective, simulated population, and treatment duration were the most common items, whereas time horizon and utilities were systematically different. These differences conduct to important range in ICER estimations (for instance, between £43,225 for NICE, €107,407 for HAS, $142,861 for CADTH for KEYTRUDA® (OC)). Heterogeneity is observed in the methodology of cost-effectiveness analyses submitted for a same product to the three considered HTA bodies. The differences in some key structural choices and hypotheses lead to heterogenous ICERs estimations, key driver for evidence-based guidance and reimbursement process.